Preparation of N-arylmethyl aziridine derivatives, 1,4,7,10-tetraazacyclododecane derivatives obtained therefrom and N-arylmethyl-ethanol-amine sulphonate esters as intermediates

ABSTRACT

Aziridines may be subjected to a cyclooligomerization reaction to produce polyazacycloalkane compounds useful for example in the preparation of chelating agents for use in diagnostic imaging contrast agents. N-benzyl-aziridine in particular is useful as it can be cyclotetramerized and debenzylated to yield cyclen, a key intermediate in chelating agent preparation. The invention provides a particularly attractive route to production of N-benzyl and other N-arylmethyl aziridines of formula (I) where each R 1  is independently hydrogen or a group AR and Ar is an optionally substituted phenyl group. The process comprises reacting a purified N-arylmethylethanolaminesulphonate ester with a base. N-arylmethyl-ethanolamine sulphonate ester of the formula R&#39;NHCH 2  CH 2  OSO 3  H, wherein the N-arylmethyl group R&#39; is an N-(bisarylmethyl) or N-(triarylmethyl) group, as intermediates. In a further aspect, the invention provides compounds of formula (II) ##STR1## where Ar and R 1  are as hereinabove defined and at least two differing ArCHR 21  moieties are present.

This application is a 371 of PCT/GB96/00552, filed Mar. 8, 1996.

This invention relates to a novel process for the preparation ofN-arylmethyl-aziridines, in particular N-benzyl-aziridine andN-benzhydryl-aziridine, and to the use of such aziridines.

In the field of magnetic resonance imaging, various lanthanide chelatesof cyclen-derivative macrocyclic chelating agents have been proposed.Two, GdHP-DO3A (ProHance from Squibb) and GdDOTA (Dotarem from Guerbet),are available commercially. These macrocyclic chelating agents formparticularly stable chelate complexes with the contrast-generatingparamagnetic metal ions and thus are suitable carriers for the metalions to ensure appropriate biodistribution and elimination.

Cyclen itself (1,4,7,10-tetraazacyclododecane) is a key and somewhatexpensive intermediate in the preparation of these macrocyclic chelants.

Cyclen's tetraaza macrocycle can be prepared by a variety of syntheticroutes, for example via diamine:diamine or triamine:monoamine cycliccondensations such as are described by Tweedle in EP-A-232751 andEP-A-292689. However in 1968 Hansen et al reported thattetrabenzylcyclen could be produced in good yield bycyclo-tetramerization of N-benzylaziridine.

The reaction described by Hansen et al in J. Heterocycl. Chem 5:305(1968) involved refluxing a mixture of 10 g of N-benzyl-aziridine and0.05 g of p-toluenesulphonic acid (PTSA) in 75 ml of 95% alcohol for sixhours.

Cornier et al (in U.S. Pat. No. 3,828,023) and Ham (in a chapterentitled "Polymerization of Aziridines" in "Polymeric Amines andAmmonium Salts", Ed. Goethels, Pergamon, 1980) confirmed thatcyclo-tetramerization of arylmethyl-aziridines occurs. Tsukube in J.Chem. Soc. Perkin Trans I 1983, 29-35 reported high yields fortetra-N-benzyl-cyclen using acid-catalysed cyclotetramerization ofN-benzyl-aziridine using the reaction conditions of Hansen (supra).

Arylmethyl groups, such as benzyl groups, are frequently used asprotecting groups in organic syntheses and selective removal of suchgroups represents straightforward chemistry. Since in this fashion thering nitrogens of a tetra-(N-arylmethyl)-cyclen can be "deprotected" toyield cyclen, N-arylmethyl-aziridine tetramerization offers a simple andattractive route in the preparation of macrocyclic chelating agents foruse in diagnostic contrast agents.

Several methods for the production of the N-arylmethyl-aziridinestarting materials are known in the literature. Thus Appel et al in ChemBer 107:5-12 (1974) describe the reaction of N-benzylethanolamine withtriethylamine, carbon tetrachloride and triphenylphosphine: ##STR2##

Appel et al reported a yield of 66% for this reaction. However repeatingthe process using N-benzylethanolamine supplied by Aldrich, yields ofonly 39 to 45% were obtained. The best results were obtained when extraextraction steps were employed and the crude extract solution wascombined with solid KOH before and during the rotary evaporation. TheAppel process moreover has a number of severe disadvantages, including(1) the generation of large quantities of (C₆ H₅)₃ PO and HN(C₂ H₅)₃ Clas by-products, (2) the use of carbon tetrachloride a material becomingincreasingly expensive and difficult to use as a result of environmentprotection regulations, and (3) the lengthy reaction time of 14 hours,the necessity for temperature control at 12° C. during cyclization andthe overall synthesis and work up time of about three days.

Pfister, in Synthesis 969-970 (1984), described a one-pot synthesisinvolving reaction of N-benzylethanolamine, triphenylphosphine anddiethylazodicarboxylate: ##STR3##

This reaction however gave only a very poor yield of 18%.

In 1969, Langlois et al in Tetrahedron Letters 25:2085-2088 (1969)reported a two-step synthesis from benzylamine: ##STR4##

Again however the yield at 45% was poor.

In U.S. Pat. No. 3,855,217 Thill proposed the production ofN-benzyl-aziridine by the reaction of aziridine itself with a benzylhalide. The same process was reported by Tsukube (supra). While thereported yields were good, the use of aziridine as a starting materialis highly undesirable. Thus the entry for aziridine in The Merck Index,11th Edition, page 600, 1989 carries the caution "Strongly irritating toeyes, skin, mucous membranes. Can be a skin sensitizer. This substancehas been listed as a carcinogen by OHSA. Fed. Reg. 39, 3757 (1974)."

Thus there is a need for a simple, environmentally acceptable and yetgood yield process for N-arylmethyl-aziridine production which willyield a product suitable for use in a cyclo-tetramerization reactions toyield tetra(arylmethyl)cyclen.

We have now found that such a process is provided by the treatment of apurified N-(arylmethyl)ethanolamine-sulphonate ester with a base. Thesulphonate ester itself can be prepared by treatment of anN-arylmethylethanolamine with sulphuric acid and this optionally is aninitial step in the process of the invention.

Thus, viewed from one aspect, the invention provides a process for thepreparation of an N-arylmethyl-aziridine of formula I ##STR5## (whereeach R₁ independently is hydrogen or a group Ar and Ar is an optionallysubstituted phenyl group), said process comprising reacting a purifiedN-arylmethylethanolamine-sulphonate ester with a base.

In the N-arylmethyl-aziridines prepared according to the invention,preferably one R₁ group is hydrogen, and especially preferably both arehydrogen. Particularly preferably, the product of the process of theinvention will be N-benzyl-aziridine or N-benzhydryl-aziridine, thecompounds of formula I where Ar is an unsubstituted phenyl group.

As mentioned above, the process of the invention optionally includes theprecursor step of generation of the sulphonate ester by reaction of anN-arylmethylethanolamine with sulphuric acid. TheN-arylmethyethanolamine starting compound if not available commerciallycan readily be prepared by reaction of the corresponding arylmethylaminewith 2-chloroethan-1-ol.

The N-(bisarylmethyl)-ethanolamine sulphonate esters and theN-(triarylmethyl)-ethanolamine sulphonate esters are themselves novelcompounds and form a further aspect of the present invention.

Generation of the sulphonate ester is preferably carried out in asolvent, for example water at a temperature in the range 80 to 150° C.,for example 50 to 100° C. The acid concentration used is preferably 7.25to 8 molar, especially about 7.7 molar and the acid andN-(arylmethyl)ethanolamine reagents are conveniently used in a molarratio of about 1:1. The reaction is relatively rapid, and may take onlya matter of seconds to yield the sulphonate ester.

Where the ester is to be isolated (i.e. purified) before reaction withthe base, this may be done by softening the solid mass with ethanol,grinding with ethanol, filtering and drying. In this way yields of 74%of a very pure product have been obtained.

Isolation of the sulphonate ester is straightforward since the esterprecipitates out of aqueous solution.

The base used in the process of the present invention may be an organicor inorganic base, preferably an alkali metal hydroxide such as sodiumhydroxide.

Reaction with the base is preferably effected in a solvent or solventmixture, e.g. water. Solutions of the base and the sulphonate ester maybe rapidly mixed to produce a reaction mixture. The reaction isconveniently effected at elevated temperature, e.g. 50 to 150° C.,especially about 80° C., and for a period of 1 to 5 hours, particularly2 to 3 hours.

The N-arylmethyl-aziridine product can be taken up in an organic solventsuch as ether and subsequently isolated by solvent distillation,preferably in the presence of an acid neutralizing agent, e.g. KOHpellets.

Since the stability of the N-arylmethyl-aziridine seems to be reduced bythe presence of N-arylmethylethanolamine, it is important that theproduct should be distilled carefully and stored over an acidneutralizing agent (preferably KOH) if it is not to be used immediatelyfor cyclo-tetramerization.

Product removal from the reaction mixture is preferably effected duringthe reaction with the base, for example by steam distillation. Howeverthis may require fresh solvent (water) to be added to the reactionmixture if the reagents show signs of crystallizing out. The product maybe removed from the distillate by solvent layer separation, organicsolvent (ether) extraction of the aqueous phase, combination and dryingof the organic phases, and removal of the organic solvent by rotaryevaporation in the presence of KOH and vacuum distillation in thepresence of KOH.

By these methods, yields of 85% of N-benzyl-aziridine (relative to thesulphonate ester) have been achieved.

The overall reaction scheme may thus for example be: ##STR6## where R'is the arylmethyl group.

The sulphonate ester formation and subsequent base treatment give astheir only by-products water and sodium sulphate, both innocuousmaterials.

The process of the present invention thus has several significantadvantages over the prior art syntheses, in particular the avoidance ofundesirable solvents such as carbon tetrachloride, the generation onlyof innocuous by-products, the non-necessity for temperature controlduring the cyclization step, the short preparation and work-up times,the production of a highly pure product, and the good yields obtained.

As mentioned above, it is known that N-arylmethyl-aziridines can becyclo-tetramerized to yield tetra-(N-arylmethyl)-cyclens. However theuse of the resulting cyclic tetramers for the generation of cyclenitself for subsequent use in the product of macrocyclic chelating agentshas not previously been proposed. Thus viewed from a further aspect, thepresent invention also provides the use of N-arylmethyl-aziridines forthe manufacture of cyclen and cyclen-based macrocyclic chelants andchelates thereof. Viewed from a yet further aspect, the invention alsoprovides a method of preparation of cyclen and cyclen derivativescomprising (i) cyclo-tetramerizing an N-arylmethyl-aziridine; (ii)cleaving arylmethyl groups from the resulting cyclen derivative; (iii)optionally, N-alkylating the resulting product; and (iv) optionally,metallating the N-alkylated product.

Step (i) above is preferably effected in a solvent and in the presenceof an acid catalyst. As the solvent there may for example be used water,methanol, ethanol, propanol, butanol, acetonitrile, dichloromethane,1,2-dichloroethane, toluene or mixtures thereof. Ethanol however ispreferred. As the catalyst, BF₃, or strong protic acids such as H₂ SO₄,H₃ PO₄ and HCl or acidic macroreticular resins such as Amberlyte XN-1010and Amberlyte 15 may be used but PTSA is preferred, especially at 0 to10% by weight relative to the aziridine, particularly 2 to 7% and moreparticularly 2.5 to 3.5% by weight. The reaction is preferably effectedat elevated temperatures, e.g. 50 to 150° C., especially 60 to 80° C. orunder reflux.

The initial aziridine concentration is preferably in the range 0.01 to5M, especially 0.1 to 2M and particularly about 0.5M or about 1M as inthis way the yield of the N-protected cyclen is optimized.

The reaction is preferably effected for less than 20 hours, e.g. 2 to 10and especially about 6 hours as increasing the reaction time causes anincrease in production of undesired dimers.

The aziridine used in step (i) may be a single compound; howeveralternatively a mixture of arylmethyl-aziridines may be used to producea hetero-protected cyclen. In this regard, mixtures ofN-benzyl-aziridine and N-benzhydryl-aziridine are particularlypreferred. The resulting hetero-protected cyclens are novel compoundsand form a further aspect of the invention. Thus, viewed from thisaspect the invention provides compounds of formula II ##STR7## where Arand R₁ are as hereinbefore defined and at least two differing ArCHR₁moieties are present.

In the compounds of formula II, it is particularly preferred that eitherone ArCHR₁ moiety is benzyl and the other three are benzhydryl or thatone is benzhydryl and the other three are benzyl. Since debenzylationand debenzhydrylation can be performed relatively selectively, suchcompounds have great potential as intermediates in the production ofcyclen derivatives having three nitrogens substituted by one form ofsubstituent and the fourth by a different substituent, for example as inDO3A and HPDO3A and as in the DO3A dimers recently proposed by NycomedSalutar and by Schering as chelants for high relaxivity MR contrastagents.

Where heterotetramerization is desired, step (i) will be performed usingthe different aziridines in molar ratios such as to give the optimumyield of the desired substitution pattern. The optimum ratio can bedetermined by simple trial experimentation beginning with molar ratioscorresponding to the ratio of the corresponding arylmethyl groups in thedesired end product.

Step (ii) may be effected using standard amine deprotection techniques,for example reductive deprotection over a metal catalyst. Where benzyland benzhydryl protective groups are present, reductive deprotection mayselectively remove the benzyl groups first. Particularly conveniently,reductive deprotection may be effected by hydrogenation over apalladium/charcoal catalyst. Alternatively, one may use cyclohexene anda palladium/charcoal catalyst. If desired, partial deprotection may beeffected by limiting the quantity or activity of reductant used so as toyield for example monoprotected or tri-protected cyclen. Alkylation ofsuch partially deprotected cyclens can be followed by furtherdeprotection and if desired further N-alkylation steps to yieldheteroalkylated cyclen derivatives such as DO3A or HPDO3A.

Step (iii), the N-alkylation step, can be used to introduce desiredalkyl or substituted alkyl groups on to the macrocyclic skeleton andagain conventional alkylation techniques may be used, for exampleinvolving reaction with an alkyl halide R₂ -Hal (where Hal is a halogenatom such as chlorine ox bromine and R₂ is an alkyl group optionallysubstituted, for example by hydroxy, alkoxy or aryl groups or by chelantmoieties, such as carboxamide or phosphonamide groups or carboxyl orphosphonic acid groups (optionally protected by ester groups)) or R₂ maybe an amphiphilic aralkyl group comprising a N, S, O or P interruptedC₂₋₂₅ alkylene chain, e.g. a polyalkylene oxide chain. The alkyl oralkylene moieties in R₂ will unless otherwise stated, convenientlycontain 1 to 12, preferably 1 to 6, carbon atoms and any chelant moietywill preferably be on the alpha or beta carbon. If a protected chelantgroup is introduced in this fashion, it may subsequently be deprotected,for example by ester cleavage to make the group available formetallation.

Where R₂ is an amphiphilic group, it may for example be a group L--Ar¹(--AH)_(n) where each L is an C₂₋₂₅ -alkylene linker wherein at leastone CH₂ moiety is replaced by X¹ or a group X¹ (CH₂ CH₂ X¹)_(u) (where uis a positive integer) such as X¹ CH₂ CH₂ X¹, X¹ CH₂ CH₂ X¹ CH₂ CH₂ X¹,X¹ CH₂ CH₂ X¹ CH₂ CH₂ X¹ CH₂ CH₂ X¹, etc), and wherein L is optionallyinterrupted by a metabolizable group M but with the provisos that theterminus of L adjacent the cyclen ring is CH₂ and that the terminus of Ladjacent Ar¹ is X¹ or a CH₂ group adjacent or separated by one CH₂ froma group X¹ (thus for example the L--Ar¹ linkage may be L¹ --X¹ --Ar¹, L¹--CH₂ -Ar¹, L¹ --X¹ CH₂ --Ar¹ or L¹ --X¹ CH₂ CH₂ --Ar¹, where L¹ is theresidue of L);

each Ar¹ is an aryl ring optionally substituted by or having fusedthereto a further aryl ring;

each AH is a protic acid group, preferably an oxyacid, e.g. a carbon,sulphur or phosphorus oxyacid or a salt thereof;

each X¹ is O, S, NR₃ or PR₃ ;

each R₃ is hydrogen, alkyl or aryl;

and n is a positive integer for example 1, 2 or 3.

Metallation in step (iv) may also be effected by conventional methods,for example as described in the patent literature relating to MRcontrast agents (see for example EP-A-71564, EP-A-130934, EP-A-165728,EP-A-258616 and WO-A-86/06605.

The choice of metal ions to be complexed will depend upon the intendedend use for the chelate complex. Especially preferred are ions of metalsof atomic numbers 22 to 32, 42 to 44, 49 and 57 to 83, in particular Gd.

Where the chelate is to be used as an MR contrast agent, the chelatedmetal species is conveniently a paramagnetic ion of a transition metalor a lanthanide, preferably having an atomic number of 21 to 29, 42, 44or 57 to 71. complexes of Eu, Gd, Dy, Ho, Cr, Mn and Fe are especiallypreferred and Gd³⁺, Mn²⁺ and Dy³⁺ are particularly preferred ions. Foruse as contrast agents in MRI, the paramagnetic metal species isconveniently non-radioactive as radioactivity is a characteristic whichis neither required nor desirable.

Where the chelate complex is to be used as an X-ray or ultrasoundcontrast agent, the metal is preferably a heavy metal such as anon-radioactive metal with an atomic number greater than 37, preferablygreater than 50, for example Dy³⁺.

Where the metal complex is to be used in scintigraphy or radiotherapy,the chelated metal species must of course be radioactive and anyconventional complexable radioactive isotope, such as ^(99m) Tc or ¹¹¹In for example may be used. For radiotherapy the chelated metal may forexample be ¹⁵³ Sm, ⁶⁷ Cu or ⁹⁰ Y.

The aziridine tetramerization reaction can if desired be driven byremoval of the tetramer and re-equilibration of the remaining fluidreaction mixture.

While a tetra-(N-arylmethyl)-cyclen tetramer product will generallyprecipitate out, cyclic tetramers produced using other aziridines may becaused to separate out, e.g. by metallation, for example with nickel orcalcium or other appropriately sized metal ions, whereupon the remainingreaction mixture may be re-equilibrated for example by heating with anacid, generally a strong acid. Thus viewed from a further aspect theinvention provides a process for aziridine cyclotetramerization whichprocess comprises oligomerizing an aziridine (preferably but notnecessarily an arylmethylaziridine), separating a cyclic tetramerproduct from the reaction mixture, heating the residual reaction mixturewith an acid, and separating out further cyclic tetramer product fromthe reaction mixture. Re-equilibration may be effected repeatedly toincrease tetramer yield.

In the cyclooligomerization process, using N-benzyl-aziridine the mostprominent cyclooligomer product is1,4,7,10-tetra(N-benzyl)-tetraazacyclododecane, and the next mostpredominant product present in the reaction mixture is1,4,7,10,13-penta(N-benzyl)-pentaazacyclopentadecane. The presence ofthis was confirmed by GPC co-injection of an authentic sample of1,4,7,10,13-penta(N-benzyl)-pentaazacyclo-pentadecane.

The cyclization reaction can be steered towards the production of othercyclic oligomers than the tetramer by modification of the reagents andprocess conditions, eg. the TACN trimer or the cyclic pentamer. Byappropriate selection of the pH and the arylmethyl groups in theaziridine reagents, one can control the optimal ring size andsubstitution pattern in the cyclooligomeric product. Thus differentarylmethyl groups produce different distributions of cyclic oligomers.For example, using N-benzhydryl aziridine one obtains a substantialyield of the cyclic pentamer. Moreover, it has been found that pHmodification, e.g. by protonation of the aziridine reagent, or a portionthereof for example 25%, can result in the cyclic trimers and pentamersbeing produced in reasonable yield. The cyclic trimers and pentamers areof considerable commercial interest and this process for theirpreparation is a further aspect of the present invention. Viewed fromthis aspect the invention provides a process for aziridineoligomerization (preferably but not essentially of N-arylmethylaziridines) which process comprises cyclooligomerizing an at leastpartially protonated aziridine and collecting the cyclic pentamer thusformed.

All patent and scientific publications mentioned above are incorporatedherein by reference.

The invention is illustrated further by reference to the followingnon-limiting Examples and to the accompanying drawings in which:

FIG. 1 is a graph showing the effect of initial aziridine concentrationon N-benzylaziridine cyclooligomer formation;

FIG. 2 is a graph showing the effect of initial concentration of theacid catalyst PTSA on N-benzylaziridine cyclooligomer formation;

FIG. 3 is a graph showing the effect of reaction temperature onN-benzylaziridine cyclooligomer formation;

FIG. 4 is a graph showing the effect of initial aziridine concentrationon N-benzhydrylaziridine cyclooligomer formation;

FIG. 5 is a graph showing the effect of initial concentration of theacid catalyst PTSA on N-benzhydrylaziridine cyclooligomer formation; and

FIG. 6 is a graph showing the effect of reaction temperature onN-benzhydrylaziridine cyclooligomer formation.

In the Figures open diamonds represent converted aziridine, opentriangles the cyclic dimer, solid triangles the cyclic trimer, soliddiamonds the cyclic tetramer, solid circles the cyclic pentamer and opencircles the cyclic hexamer and higher oligomers. FIGS. 1 and 4 are logplots for a reaction mixture containing 0.5 weight % PTSA (relative tothe aziridine), 95% ethanol as solvent refluxed for 6 hours. FIGS. 2 and5 are plots for reaction mixtures containing 1 and 0.25M aziridinerespectively, 95% ethanol as solvent, refluxed for 6 hours. FIGS. 3 and6 are plots for reaction mixtures containing 1 and 0.25M aziridinerespectively, 0.5 weight % (relative to aziridine) PTSA, kept for 6hours at the reaction temperature.

EXAMPLE 1

N-Benzylethanolamine-sulphonate ester

N-Benzylethanolamine (30.12 g, 0.2 mol from Aldrich) was dissolved in 15ml of distilled water and the solution was cooled to 0° C. in a salt-icebath. In a three-neck flask (equipped with a thermometer to measurereaction temperature, magnetic stirbar and air-inlet adaptor) a solutionof sulphuric acid was prepared by slow addition of 96.5% sulphuric acid(20.52 g, 0.2 mol) to distilled water (11 ml) with stirring and coolingof the flask in a salt-ice bath. The gas-inlet adaptor was connected toa filter trap, cooled in salt-ice, and the filter flask was connected toa water aspirator. The N-benzyl-ethanolamine solution was then addedslowly to the sulphuric acid solution with constant stirring andcooling. The brownish-yellow mixture was heated at 80° C. under wateraspiration vacuum. After most of the water was removed, a solid formedand heat was removed. After a few seconds, the reaction mixturesolidified and the temperature rose sharply to 140° C. The solid wascooled to ambient temperature and softened with 100 ml of absoluteethanol. The solid was removed from the reaction flask, ground with anadditional 50 ml of ethanol and the white sulphonate ester was filteredand dried. Yield 34.3 g (74%). ¹ H NMR (δ, 360 MHz, acetone-D₆ /D₂ O):3.40 (m, 2H, --NCH₂ CH₂ O--), 4.26 (m, 2H, --NCH₂ CH₂ O--), 4.36 (2, 2H,--CH₂ Ph), 7.40 (m, 3H, --CH₂ Ph) and 7.56 (m, 2H, --CH₂ Ph).

EXAMPLE 2

N-Benzylaziridine

In a three-neck flask (with heating mantle, mechanical stirrer, additionfunnel and distillation head with condenser attached to a RB receiverflask containing potassium hydroxide pellets and 100 ml of toluene orether and cooled with an iced bath) N-benzylethanolamine-sulphonateester (30.7 g, 0.13 mol) was dissolved in 200 ml of water by stirringfor 30 minutes at 50° C. The solution was cooled to ambient temperatureand then a solution of sodium hydroxide (28.0 g dissolved in 40 ml ofwater) was added rapidly via the addition funnel to the vigorouslystirred ester solution. The reaction mixture was gradually heated anddistillate (water and N-benzyl-aziridine) collected in the cooledreceiver flask. During the steam distillation, water was added to thereaction flask whenever the reaction mixture showed signs ofcrystallizing and bumping. After 2 to 3 hours, the distillation wascomplete. The distillate was poured into a separation funnel and thetoluene/aziridine layer was separated. The aqueous layer was extractedthree times with 50 ml of toluene. The toluene phases were combined anddried over sodium hydroxide pellets. The toluene solvent was removed ona roto-vap in the presence of potassium hydroxide pellets. (Ether may beused in place of toluene). The concentrate was vacuum distilled in thepresence of KOH pellets using a 7.5 inch Vigreux column. The fractionboiling at 56 to 58° C./2 mmHg was collected and stored over potassiumhydroxide pellets. Yield 14.9 g (81% using ether). The procedure ofExample 2 required 13 hours. ¹ H NMR (δ, 360 MHz, CDCl₃): 1.16 (m, 2H,aziridine ring H), 1.71 (m, 2H, aziridine ring H), 3.27 (s, 2H, --CH₂Ph), and 7.14 (m, 5H, --CH₂ Ph); ¹³ C NMR (δ, 90 MHz, {¹ H}, CDCl₃) 24.5(aziridine ring C), 64.7 (--CH₂ Ph), 126.8, 127.1, 128.1 and 139.4(--CH₂ Ph).

EXAMPLE 3

N,N'N",N'"-Tetrabenzylcyclen

(a) N-Benzyl-aziridine (2.05 g, 15.4 mmol) was placed in a 100 mlone-neck roundbottom flask with magnetic stir bar and then 15.5 ml of asolution of p-toluenesulphonic acid monohydrate (PTSA from Aldrich;solution prepared by dissolving 0.253 g PTSA in 37.5 ml of 95% ethanol)was added. A water-cooled condenser was attached. The PTSA thusrepresented 5% by weight of the N-benzyl-aziridine. The reaction mixturewas refluxed for 6 hours and then cooled to ambient temperature. Theresulting white solid was filtered and dried and subsequentlyrecrystallized from 150 ml of 2:1 methanol/dichloromethane. Yield 0.78 g(39%). ¹ H NMR (δ, 360 MHz, CDCl₃): 2.66 (s, 16H, cyclen ring H), 3.41(s, 8H, --CH₂ Ph), and 7.17 (m, 20H, --CH₂ Ph); ¹³ C NMR (δ, 90 MHz, {¹H}, CDCl₃): 53.0 (cyclen ring C), 60.1 (CH₂ Ph), 126.8, 128.3, 129.2 and140.4 (CH₂ Ph); Mass spec (EI, m/e): 532 (M⁺). mp 144-145° C.(uncorrected).

(b) N-Benzylaziridine (9.0 g, 67.7 mmol) was placed in a 250 ml,one-neck round bottom flask with a magnetic stir bar and then 68.5 mL of95% ethanol and 0.23 g p-toluenesulfonic acid monohydrate (PTSA fromAldrich) were added. A water-cooled condenser was attached. The PTSAthus represented 2.5% by weight of the N-benzylaziridine. The reactionmixture was refluxed for 6 hours and then cooled to ambient temperature.The resulting white solid was filtered, dried and subsequentlyrecrystallized from about 300 mL of 1:1 methanol/dichloromethane.Isolated yield 3.0 g (33%). ¹ H NMR spectra as in Example 3(a) above.

(c) The title compound was produced in 35.1 yield (33.8 mg) (yield % isbased on converted aziridine, by gel permeation chromatography using aninternal standard with experimentally determined response factors) byreaction of N-benzylaziridine (0.1 g, 0.75 mmol) with 0.75 mL of asolution of p-toluenesulfonic acid [prepared by dissolving 27.0 mg ofp-toluenesulfonic acid monohydrate (Aldrich) in 7.5 mL of 95% ethanol]at reflux temperature for 6 hours. The PTSA thus represented 2.55. byweight of the N-benzylaziridine.

N,N',N",N'",N""-pentabenzyl-1,4,7,10,13-pentaazacyclopentadecane wasobtained in a 6.1 yield (5.8 mg) (from gel permeation chromatography,with yield percentage being based on converted aziridine) from thecyclooligomerization mixture of Example 3(b).

Cyclic oligomers of N-benzylaziridine

The yields of cyclic oligomers using the methods of and based on Example3 were determined by using gel permeation chromatography. Absoluteamounts were determined by comparison to authentic samples of thestarting aziridine and the cyclic-(N)₂ to cyclic-(N)₅ oligomers. The sumof higher oligomers was then obtained by difference.

FIG. 1 of the accompanying drawings shows the yields of macrocyclics asa function of starting material concentration.

FIG. 2 of the accompanying drawings shows the yields of macrocyclics asa function of acid catalyst concentration.

FIG. 3 of the accompanying drawings shows the yields of macrocycles as afunction of reaction temperature.

The influence on the yields of different macrocycles, using the methodsbased on Example 3, of different acid catalysts and different reactionmedia are shown in Tables 1 and 2 below. Table 1 shows the influence ofdifferent catalysts on the cyclooligomer concentrations. Table 2 showsthe influence of the reaction medium on the cyclooligomerconcentrations.

                  TABLE 1                                                         ______________________________________                                        Influence of Different Acid Catalysts on the                                    Cyclooligomer Fractions (Based on Utilized N-Benzyl-                          aziridine, in wt %). (1M, 0.5 wt % catalyst, 6 hour, reflux)                          Aziridine   c-N.sub.2                                                                          c-N.sub.4                                                                            c-N.sub.5                                                                          >N.sub.5                                 Catalyst         Conversion  Yield     Yield    Yield     oligomers         ______________________________________                                        PTSA  51.7        0.3    23.6   6.0  70.2                                       H.sub.2 SO.sub.4  55.9       0.0       17.0     4.7       78.3                HOAc              40.0       0.2        5.2     1.5        0.0                H.sub.3 PO.sub.4  61.3       0.7       17.4     4.7       77.2                HCl               66.1       3.6       13.8     3.8       78.8              ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Influence of Reaction Medium on the Cyclooligomer                               Fractions (Based on Utilized N-Benzyl-aziridine,                              in wt %). (1M, 0.5 wt % PTSA catalyst, 6 hour, reflux)                        Reaction  Aziridine   c-N.sub.2                                                                          c-N.sub.4                                                                            c-N.sub.5                                                                          >N.sub.5                               Medium     Conversion  Yield     Yield     Yield     oligomers              ______________________________________                                        95% EtOH*                                                                             51.7        0.3    23.6   6.0  70.2                                     80% EtOH*    64.8       0.0      15.3      3.6       81.2                   ______________________________________                                         *balance water                                                           

EXAMPLE 4

Cyclen

(a) Palladium/charcoal catalyst (0.11 g, Aldrich wet 10% Pd/C, Degussatype E101NE/W), tetra-(N-benzyl)cyclen (0.1 g, 0.18 mmol) andcyclohexene (15 ml of a 1:2 cyclohexene/absolute ethanol mixtureobtained using 99% pure cyclohexene from Aldrich) were placed into aone-neck RB flask with a condenser. The mixture was refluxed for 25hours. The reaction mixture was then filtered by gravity filtrationthrough three layers of S7S#602 fine filter paper and the insolubleswere washed with three 10 mL portions of ethanol. The combined filtrateswere roto-vaped to produce the title compound. Yield 0.028 g (88%).

(b) Tetrabenzylcyclen (0.5 g, 0.9 mmol), ethanol (50 mL), and 10% Pd oncarbon (0.5 g) were loaded into a 100 mL Autoclave pressure reactor. Thereactor was pressurized to 100 psig with hydrogen for 3 hours at 80° C.The mixture was filtered to remove the catalyst and the filtrate wasconcentrated to afford pure cyclen in essentially quantitive yield(m/e=172). ¹ H NMR (δ, 360 MHz, CDCl₃): 2.35 (bs, 4H, --NH) and 2.67 (s,16H, --NCH₂ CH₂ N--); ¹³ C NMR (δ, 90 MHz, {¹ H}, CDCl₃): 46.1 (--NCH₂CH₂ N--).

EXAMPLE 5

1,4,7,10-Tetra-carboxymethyl-1,4,7,10-tetraazacyclododecane(DOTA)

To an aqueous solution of cyclen (0.16 mols in 58 mL water) was added anaqueous solution of sodium chloroacetate (0.71 mols sodium chloroacetatein 68 mL of water). This solution was stirred at 80° C. overnight whilemaintaining the pH at 9-10. After cooling to ambient temperature the pHof the solution was adjusted to 2.5 with aqueous HCl. The resultingprecipitate was collected by filtration washed with acetone and dried invacuo to afford 45.5 g of DOTA-HCl (m/e=628).

EXAMPLE 6

Sodium salt of the1,4,7,10-tetra-carboxymethyl-1,4,7,10-tetraazacyclododecane(DOTA)cradolinium(III)complex

To 300 mL of water was added 9.3 g Gd₂ O₃ (0.0256 mols) and 0.051 molsof DOTA. The solution was warmed to 90° C. and the pH was adjusted to8-9. The solution was cooled to ambient temperature and the pH wasadjusted to 7.5 with HCl. The product was precipitated with acetone,collected by filtration, and then dried in vacuo to afford 26.0 g ofwhite product.

EXAMPLE 7

N-Benzhydryl-ethanolamine

In a 500 mL round bottom flask equipped with a condenser and athermometer, 2-choroethan-1-ol (23.3 grams, 0.39 mol, Kodak),α-aminodiphenylmethane (82.0 grams, 0.45 mol, Fluka), and water (17 mL)were placed. The mixture was heated on a steam bath (ca. 90° C.) for sixhours. After cooling to ambient temperature, NaOH (15 grams, 0.37 mol)was added and the mixture heated on a steam bath for 45 minutes at ca.90° C. Water (50 mL) was then added to the solution. The resultingtwo-layered mixture was extracted with two 50 mL portions of toluene.The combined toluene extracts were dried over sodium hydroxide pelletsand the toluene then removed by rotary evaporation at reduced pressure.The residue was fractionally distilled using a 7.5 inch Vigreux column.The fraction boiling at 175-177° C./2 mm pressure was collected and thenrecrystallized from hexane. Yield 39.0 g (59% yield). ¹ H NMR (δ, 360MHz, CDCl₃) 2.32 (bs, 2H, --OH & --NH), 2.74 (m, 2H, --NCH₂ CH₂ O--),3.64 (m, 2H, --NCH₂ CH₂ O--) 4.84 (s, 1H, CHPh₂) and 7.30 (m, 10H,aromatic H); ¹³ C NMR (δ, 90 MHz, {¹ H}, CDCl₃); 49.5 (--NCH₂ CH₂ O--),61.5 (--NCH₂ CH₂ O--) 67.0 (CHPh₂), 127.2, 127.3, 128.3 and 147.5(CHPh₂) mp 69-70° C. uncorrected.

EXAMPLE 8

N-Benzhydryl-ethanolamine sulphonate ester

A suspension of N-benzhydryl-ethanolamine (24.8 grams, 0.11 mol) wasprepared in a 500 mL three-neck round bottom flask (equipped with athermometer, magnetic stir bar, and air-inlet adapter) in 60 mL ofdistilled water and the mixture cooled to 0° C. in an ice bath. Asulphuric acid solution (11.9 grams of sulphuric acid, 0.12 mol,dissolved in 10 mL of distilled water) was added slowly with constantstirring and cooling of the flask in the ice bath. The ice bath wasremoved and the resulting clear yellow solution was heated under wateraspirator vacuum. After most of the water had been removed byevaporation, the solution thickened and the temperature rose steadily.After the temperature rose to 180° C., the solution darkened in colour.The heat source was immediately removed and the mixture was allowed tocool to ambient temperature, yielding a golden brown glassy material.Distilled water (50 mL) was added, and the mixture was stirred atambient temperature for 1.5 hours until the glassy residue had changedto an off-white powdery solid. The solid was filtered and washed withseveral mL of acetone. Yield 2.9 g (41% yield) ¹ H NMR (δ, 360 MHz,acetone-D₆ /D₂ O): 3.24 (m, 2H, --NCH₂ CH₂ O--), 4.20 (m, 2H, --NCH₂ CH₂O--), 5.56 (s, 1H, CHPh₂), 7.36 (m, 10H, --CHPh₂)

EXAMPLE 9

N-Benzhydryl-aziridine

A suspension of N-benzhydryl-ethanolamine sulphonate ester (13.6 grams,44.3 mmol) in distilled water (140 mL) was placed in a 500 mLthree-necked flask fitted with an addition funnel and mechanicalstirrer. The mixture was heated to ca. 50° C. and stirred until most ofthe solid had dissolved. A solution of sodium hydroxide (8.7 grams, 220mmol) in distilled water (30 mL) was then added with vigorous stirring.Toluene (100 mL) was added to the mixture and the resulting two-phasemixture was stirred vigorously for one hour while cooling to ambienttemperature. The mixture was poured into a separatory funnel and thetoluene/N-benzhydryl-aziridine layer was removed. The aqueous layer wasextracted three times with 50 mL portions of toluene. The combinedtoluene solutions were dried over NaOH pellets. The toluene solvent wasremoved on a rotary evaporator at reduced pressure and the crude productwas recrystallized from hexane. (Alternatively one may use ether ratherthan toluene: here the reaction mixture, after the addition of 30 mLdistilled water was gradually heated and distillate (water andN-benzhydrylaziridine) collected in the cooled receiver flask. Afterabout 3-4 hours, (when the distillate contained no more oil drops),distillation was stopped and the reaction mixture was allowed to cool toambient temperature. The distillate was poured into a separatory funneland mixed with 100 mL ether. The aziridine-ether layer was separated.The aqueous layers from the distillate and the cooled reaction mixturewere extracted twice with ether. The ether phases were combined anddried over sodium hydroxide pellets. The ether solvent was removed on arotary evaporator at reduced pressure and the crude product wasrecrystallized from hexane.) Yield 6.2 g (66%). ¹ H NMR (δ, 360 MHz,CDCl₃): 1.33 (m, 2H, aziridine ring H), 1.87 (m, H, aziridine ring H),3.33 (s, H, CHPh₂), and 7.26 (m, 5H, CHPh₂); ¹³ C NMR (δ, 90 MHz, {¹ H},CDCl₃) 28.1 (aziridine ring C), 78.9 (CHPh₂), 127.1, 127.4, 123.4 and143.3 (CHph₂). mp 56-58° C. uncorrected. Mass spectrum (EI, m/e): 209(M⁺).

EXAMPLE 10

N,N',N",N'"-Tetrabenzhydryl-cyclen

(a) Analogously to Example 3, the title compound was produced in 40%crude yield (25% relative yield by gel permeation chromatography usingan internal standard with experimentally determined response factor) byreaction of N-benzhydryl-aziridine (78.6 mg, 0.37 mmol) with 0.5% byweight of PTSA in ethanol (4 mL). ¹ H NMR (δ, 360 MHz, CDCl₃): 2.75 (s,16H, cyclen ring H), 4.62 (s, 4H, --CHPh₂), and 7.13 (m, 40H, CHPh₂);Mass spec (EI, m/e): 837 (M⁺). mp 200-202° C. uncorrected.

The title product tetramer can be deprotected, alkylated and metallatedanalogously to the tetrabenzyl-cyclen reactions of Examples 4 to 6.

N,N',N",N'",N""-Pentabenzhydryl-1,4,7,10,13-pentaaza-cyclopentadecanewas obtained in 13.7% relative yield (gel permeation chromatography)from the reaction mixture of Example 10. ¹ H NMR (δ, 360 MHz, CDCl₃):3.04 (s, 20H, macrocycle ring H), 4.52 (s, 5H, CHPh₂), and 7.15 (m, 50H,CHPh₂).

(b) Analogously to Example 3, for the synthesis of a pure sample of thetitle compound in a preparative scale the following procedure was used.N-benzhydrylaziridine (2.2 g, 10.5 mmol) with 0.35% by weight ofp-toluenesulfonic acid (7.8 mg, 0.041 mmol, Aldrich) were reacted in 95%ethanol (25 mL). After cooling the reaction mixture to ambienttemperature, the precipitated solid was filtered off and suspensed inabout 200 mL of ethanol. The suspension was filtered and the insolublematerial was collected and dried. Isolated yield 0.1 g (5%).

¹ H NMR (δ, 360 MHz, CDCl₃): 2.75 (s, 16H, cyclen ring H), 4.62 (s, 4H,--CHPh₂), and 7.13 (m, 40H, CHPh₂); Mass spec (EI, m/e): 837 (M⁺). mp200-202° C. uncorrected.

The title compound was produced in 41.1% yield (26.9 mg) (yield % basedon converted aziridine, gel permeation chromatography using an internalstandard with experimentally determined response factor) by reaction ofN-benzhydrylaziridine (78.7 mg, 0.37 mmol), 0.6 mL of a solution ofp-toluenesulfonic acid [prepared by dissolving 27.0 mg ofp-toluenesulfonic acid monohydrate (Aldrich) in 7.5 mL of 95% ethanol]and 0.9 mL of 95% ethanol at reflux temperature for 6 hours. The PTSAthus represented 2.5% by weight of N-benzhydrylaziridine.

The title product tetramer can be deprotected, alkylated and metallatedanalogously to the tetrabenzyl-cyclen reactions of Examples 4 to 6.

N,N',N",N'",N""-pentabenzhydryl-1,4,7,10,13-pentaazacyclopentadecane wasobtained in 26.5 yield (16.9 mg) based on converted aziridine (from gelpermeation chromatography) from the cyclooligomerization reactionmixture of Example 10(b). ¹ H NMR (δ, 360 MHz, CDCl₃): 3.04 (s, 20H,macrocycle ring H), 4.52 (s, 5H, CHPh₂), and 7.15 (m, 50H, CHPh₂). Massspectrum (FAB, 3-nitrobenzyl alcohol, m/e): 1046.4 (M⁺), mp 208-210°uncorrected.

It has been shown that there is a large difference in the cyclooligomerdistribution in the product mixtures obtained from stoichiometric andcatalytic protonation. A GPC chromatogram obtained on a reaction mixturefrom stoichiometric protonation (with PTSA) showed the presence of largeamounts of cyclopentamer and cyclohexamer along with trace amounts ofcyclodimer, cyclotetramer, higher oligomers or cyclooligomers, andunreacted N-benzylhydrylaziridine.

FIG. 4 of the accompanying drawings shows the N-benzhydrylcyclooligomerization as a function of initial aziridine concentration.

FIG. 5 of the accompanying drawings shows the N-benzhydrylcyclooligomerization as a function of acid concentration (PTSA).

FIG. 6 of the accompanying drawings shows the N-benzhydrylcyclooligomerization as a function of the reaction temperature.

EXAMPLE 11

N,N',N",N'",N"",N'""-hexabenzhydryl-1,4,7,10,13,15-hexaazacyclohexadecane

In a 20 mL vial, a mixture of N-benzhydrylaziridine (78.6 mg, 0.37 mmol)and p-toluene-sulfonic acid monohydrate (71.5 mg, 0.37 mmol, Aldrich)were dissolved in 2.5 mL dichloromethane (dried via distillation from P₂O₅). In another vial, N-benzhydrylaziridine (156 mg, 0.74 mmol) wasdissolved in 1.0 mL of dichloromethane. Both solutions were transferredinto two separate addition funnels attached to a 50 mL three-neck flask(equipped with a water-cooled condenser and a stir bar) containing 1.0mL of dichloromethane. Both solutions were added simultaneously into theflask with vigorous stirring. After the mixture had been refluxed for 6hours, a white solid was obtained upon the removal of the solvent byrotary evaporation at reduced pressure. The GPC analysis of the productmixture indicated the presence of title compound approximately in 59%yield based on utilized aziridine. Other by-products includedN,N',N",N'",N""-pentabenzhydryl-1,4,7,10,13-pentaazacyclopentadecane(31.3%), cyclodimer (5.3%), cyclotetramer (31.3%) and trace amounts ofhigher oligomers or cyclooligomers (% yields by gel permeationchromatography based on utilized aziridine).

                  TABLE 3                                                         ______________________________________                                        Aziridine                         >c-N.sub.5 (mostly                            conversion, %  c-N.sub.2 %  c-N.sub.4 %  c-N.sub.5 %  c-N.sub.6),           ______________________________________                                                                          %                                           91.3      5.3     3.9       31.3  59.5                                        ______________________________________                                    

EXAMPLE 12

1,7-bis(N-benzyl)-1,4,7,10-tetraazacyclododecane

Analogously to Example 4, the title compound was obtained by reactingtetra(N-benzyl)cyclen (100 mg) and 15 mL of 1:2 v/v cyclohexane/ethanolsolution in the presence of 5% Pd on alumina catalyst (Aldrich). ¹ H NMR(δ, 360 MHz, CDCl₃): 2.57 (AA'BB' spin system, 16H, cyclen ring H), 3.55(s, 4H, CHPh), and 7.30 (m, 10H, CH₂ Ph); Mass spec (EI, m/e): 352 (M⁺)

EXAMPLE 13

1,4,7-tri(N-benzyl-triazacyclononane (Tribenzyl,TACN)

In a 20 ml vial, a mixture of N-benzylaziridine (79.0 mg, 0.59 mmol),p-toluenesulphonic acid (116.0 mg, 0.59 mmol) and 5 ml of methylenechloride were stirred until all acid dissolved. In another vial,N-benzylaziridine (158.0 mg, 1.18 mmol) was dissolved in 5 ml ofmethylene chloride. Both of these solution were added simultaneouslywith vigorous stirring into a 50 ml three-neck flask (equipped with twoaddition funnels, a water-cooled condenser and a stir bar) containing 1ml of methylene chloride. After the mixture had been refluxed for 4hours, an off-white semi-solid was obtained after removing the solventby rotary evaporation at reduced pressure. The product contained amixture of cyclic dimer, trimer, tetramer, pentamer and other higheroligomers with the trimer being the most predominant product by ¹ H NMR.The ¹ H NMR values were consistent with the assigned cyclic trimer (¹ HNMR: 2.90(s) and 3.62(s); integral ratio 2:1). The various polymers maybe separated out by column chromatography.

EXAMPLE 14

Mixed aziridine cocyclization

In a 20 ml vial, a mixture of N-benzylaziridine (0.05 grams, 0.38 mmol)p-toluenesulphonic acid (0.071 grams, 0.39 mmol) and 3 ml of chloroformwere stirred until all acid dissolved. In another vial,N-benzhydrylaziridine (0.23 grams, 1.18 mmol, 3 equivalents) wasdissolved in 1 ml of chloroform. Both of these solution were transferredinto two separate addition funnels attached to a 50 ml three-neck flask(equipped with a water-cooled condenser and a stir bar). Both solutionswere added simultaneously into the flask with vigorous stirring. Afterthe mixture had been refluxed for 5 hours, a white solid was obtainedafter removing the solvent by rotary evaporation at reduced pressure.The ¹ H NMR spectral data indicated the absence of N-benzylaziridine,presence of some N-benzhydrylaziridine, and new resonances between 2-3ppm and 4-5 ppm indicative of a mixed N-alkylated cyclooligomer.

EXAMPLE 15

1,4,7-Triazacyclononane (TACN)

Tribenzyl.TACN, ethanol, and 10% Pd on carbon are loaded into a 100 mLAutoclave pressure reactor. The reactor is pressurized to 100 psig withhydrogen for 3 hours at 80° C. The mixture is filtered to remove thecatalyst and the filtrate is concentrated to afford pure TACN inessentially quantitative yield.

EXAMPLE 16

1,4,7-Tricarboxyethyl-1,4,7-triazacyclononane To an aqueous solution ofTACN (0.16 mols in 58 mL water) is added an aqueous solution of sodiumchloroacetate (0.71 mols sodium chloroacetate in 68 mL of water). Thissolution is stirred at 80° C. overnight while maintaining the pH at9-10. After cooling to ambient temperature the pH of the solution isadjusted to 2.5 with aqueous HCl. The resulting precipitate is collectedby filtration, washed with acetone, and dried in vacuo to afford themono-hydrochloride salt of1,4,7-tricarboxymethyl-1,4,7-triazacyclononane.

EXAMPLE 17

N-(4-Methylbenzyl)ethanolamine

The procedure of Example 7 was repeated using 2-chloroethanol (20.9 g,0.26 mol, Kodak), 4-methylbenzylamine (32.7 g, 0.27 mol, Aldrich), water(25 mL) and KOH (14.6 g, 0.26 mol). A white solid was crystallized fromthe concentrated solution. The crystallized product was collected bysuction filtration and recrystallized from hexanes. The filtrate wasconcentrated under reduced pressure and the residue was fractionallydistilled using a 7.5 inch vigreux column. The fraction boiling at140-144° C./9 mm pressure was collected. Total yield 15 g (35% yield). ¹H NMR (δ, 360 MHz, CDCl₃): 2.32 (s, 3H), 2.51 (broad s, 2H), 2.74 (t,2H), 3.61 (t, 2H), 3.72 (s, 2H) and 7.142 (m, 4H). ¹³ C NMR (δ, 90 MHz,{¹ H}, CDCl₃): 21.0 (--CH₃), 50.5 (--NCH₂ CH₂ O--) 53.2 (--NCH₂ CH₂O--), 60.7 (--NCH₂ Ph), 128.1, 129.1 and 143.0 (--CH₂ Ph). mp 61-62° C.uncorrected. The title compound was also prepared using the followingprocedure. In a 2L three-neck flask (equipped with a mechanical stirrerand an addition funnel) ethanolamine (91.6 g, 1.5 mol, Aldrich) and 100mL of toluene were placed. To this solution was added dropwise4-methylbenzyl chloride (70.3 g, 0.5 mol, Aldrich). The mixture wasstirred for 10 hours at room temperature. Crushed KOH (30.0 g, 0.5 mol)was added and stirring was continued for another 3 hours. Water (300 mL)was added to dissolve all solid. The mixture was poured into aseparatory funnel and the toluene layer was separated. The aqueous layerwas extracted with 50 mL portions of methylene chloride three times. Thecombined extracts were dried on anhydrous sodium sulfate and rotovapedto remove the solvents. A white solid was crystallized from theconcentrated solution. The crystallized product (34 g) was collected bysuction filtration and washed with several mL of toluene. The filtratewas concentrated under reduced pressure and the residue was fractionallydistilled using a 7.5 inch vigreux column. The fraction boiling at140-144° C./9 mm pressure was collected. Total yield isolated 46.5 g(57% yield).

EXAMPLE 18

N-(4-Methylbenzyl)ethanolamine sulphonate ester

A suspension of 4-methylbenzylethanolamine (6.0 g, 36.3 mmol) wasprepared in a 250 mL three-neck flask (equipped with a thermometer,magnetic stir bar and air inlet adapter) in 3.0 mL distilled water andthe mixture was cooled to 0° C. in an ice bath. A solution of sulfuricacid (3.56 g, 36.3 mmol, dissolved in 1.8 mL water) was added slowly tothe flask with constant stirring and cooling in the ice bath. Thereaction mixture was then heated under water aspirator vacuum. Aftermost of the water was removed at 55° C., a solid formed and the heatsource was removed. After a few seconds, the reaction mixture solidifiedand the temperature rose sharply to 130° C. The solid was cooled toambient temperature and softened with 50 mL of absolute ethanol. Thesolid was removed from the flask, ground in ethanol and the sulphonateester was filtered and dried. Yield 6.8 g (76.5% yield). ¹ H NMR (δ, 360MHz, Acetone-D₆ /D₂ O): 2.22 (s, 3H), 3.31 (t, 2H), 4.19 (t, 2H), 4.21(s, 2H) and 7.25 (m, 4H). Decomposed at 247° C.

EXAMPLE 19

N-(4-Methylbenzyl)aziridine

Analogously to Example 2, the title compound was synthesized in 93%yield (3.8 g) using N-(4-methylbenzyl)ethanolamine sulphonate ester (6.8g, 2.7 mmol, dissolved in 150 mL of distilled water) and a solution ofsodium hydroxide (6.07 g dissolved in 10 mL of water). ¹ H NMR (δ, 360MHz, CDCl₃): 1.25 (t, 2H), 1.79 (t, 2H), 2.30 (s, 3H), 3.33 (s, 2H) and7.18 (m, 4H).

EXAMPLE 20

N,N',N",N'"-Tetra(4-methylbenzyl)cyclen

The title compound was produced in 40.3% yield by reaction ofN-(4-methylbenzyl)aziridine (0.1 g, 0.7 mmol) with 2.5% by weight ofPTSA in ethanol (0.35 mL) at reflux temperature for 6 hours. The otherby-products contained cyclodimer (4.8%), cyclotrimer (0.2%),cyclopentamer (8.5%), and other higher oligomers and cyclooligomers %yields are the relative product ratios by gel permeationchromatography).

EXAMPLE 21

Comparative degrees of cyclooligomerization in Example 3 and 20

Table 4 shows the change in relative cyclooligomer product ratios as afunction of substituent on the nitrogen of the aziridine.

                  TABLE 4                                                         ______________________________________                                        Relative Product Ratios of Cyclooligomers                                       (Based on Area % from GPC Chromatogram, in %). (1M,                           2.5 wt % PTSA catalyst, 6 hour, reflux)                                                   c-N.sub.2                                                                              c-N.sub.3                                                                          c-N.sub.4                                                                            c-N.sub.5                                                                          >c-N.sub.5                              Aziridine   Yield  Yield  Yield  Yield  oligomers                           ______________________________________                                        N-Benzyl  0.6      0.0    63.4   9.7  14.1                                      N(4-methyl        4.8    0.2    40.3   8.5    53.8                            benzyl                                                                      ______________________________________                                    

We claim:
 1. A method of preparation of cyclen and cyclen derivativescomprising (i) cyclo-tetramerizing an N-arylmethyl-aziridine; (ii)cleaving arylmethyl groups from the resulting cyclen derivative; (iii)optionally, N-alkylating the resulting product; and (iv) optionally,metallating the N-alkylated product.
 2. A method as claimed in claim 1wherein the N-arylmethyl-aziridine is a compound of formula (I):##STR8## wherein each R₁ independently is hydrogen or a group Ar and Aris an optionally substituted phenyl group.
 3. A method as claimed inclaim 2 wherein step (i) is effected using p-toluenesulphonic acid as acatalyst.
 4. A method as claimed in claim 2 wherein a mixture ofN-arylmethyl-aziridines is used in step (i).
 5. A method as claimed inclaim 2 wherein N-alkylation in step (iii) is effected by reaction withan alkylating agent of formula R₂ -Hal (where Hal is a halogen atom andR₂ is an alkyl group optionally substituted by hydroxy, alkoxy or arylgroups or by chelant moieties themselves optionally protected by estergroups or R₂ is an amphiphilic aralkyl group comprising a N, S, O or Pinterrupted C₂₋₂₅ alkylene chain).
 6. A method as claimed in claim 2wherein in step (iv) the product is metallated with paramagnetictransition metal or lanthanide metal ions.
 7. A method as claimed inclaim 2 wherein the cyclo-tetramerization of step (i) is promoted byremoval of the cyclic tetramer from the reaction mixture andre-equilibration of the remaining reaction mixture.
 8. A method asclaimed in claim 2 wherein step (i) is effected using p-tolunesluphoncacid as a catalyst.
 9. A method as claimed in claim 2 wherein a mixtureof N-arylmethyl-aziridines is used in step (i).
 10. A method as claimedin claim 8 wherein a mixture of N-arylmethyl-aziridines is used in step(i).
 11. A method as claimed in claim 7 wherein N-alkylation in step(iii) is effected by reaction with an alkylating agent of formula R₂-Hal, where Hal is a halogen atom and R₂ is an alkyl group optionallysubstituted by hydroxy, alkoxy or aryl groups or by chelant moietiesthemselves optionally protected by ester groups or R₂ is an amphiphilicaralkyl group comprising a N, S, O or P interrupted by C₂₋₂₅ alkylenechain.
 12. A method as claimed in claim 2 wherein N-alkylation in step(iii) is effected by reaction with an alkylating agent of formula R₂-Hal, where Hal is a halogen atom and R₂ is an alkyl group optionallysubstituted by hydroxy, alkoxy or aryl groups or by chelant moietiesthemselves optionally protected by ester groups or R₂ is an amphiphilicaralkyl group comprising a N, S, O or P interrupted by a C 2-25 alkylenechain.
 13. A method as claimed in claim 8 wherein N-alkylation in step(iii) is effected by reaction with an alkylating agent of formula R₂-Hal, where Hal is a halogen atom and R₂ is an alkyl group optionallysubstituted by hydroxy, alkoxy or aryl groups or by chelant moietiesthemselves optionally protected by ester groups or R₂ is an amphiphilicaralkyl group comprising a N, S, O or P interrupted by a C₂₋₂₅, alkylenechain.